This proposal stems from the observation made by the principal investigator that macrophage- specific expression of human apolipoprotein E in apoE-null (Apoe-/-) mice reduces the development of atherosclerosis. However it is not known if the level of apoE normally produced by macrophages in ApoE +/+ mice gives maximal protection. Therefore the investigators have designed their experiments to answer four key questions: a) Will increased levels of expression of apoE by macrophages in wild-type mice decrease the formation of atherosclerotic lesions? b) Will expression of apoE in macrophages after the development of atheroslerotic lesions cause lesions to regress or halt their progression? c) Does expression of apoE in atherosclerotic lesions enhance cholesterol efflux? d) Are there apoE isoform-specific differences on atherosclerotic lesion formation and regression? The proposed specific aims are therefore as follows:. Here they will generate C57BL/6 mice with macrophage-1) To determine the effect of macrophage-specific over-expression of apoE3 on the formation of atherosclerotic lesions expression of apoE3, and then they will examine the effect this expression on diet-induced atherosclerosis. 2) To determine the effect of macrophage-specific expression of human apoE3 on existing atherosclerotic lesions in wild-type and in ApoE-/- mice. Here they will produce wild-type and ApoE-/- mice with tetracycline- regulated, macrophage-specific expression of apoE. They will then determine the effect of ApoE3 expression on atherosclerotic lesion progression or regression in these mice. Finally they will determine the effect of macrophage-specific expression of ApoE3 on the release of cholesterol from atherosclerotic lesions. 3) To determine if ApoE2, ApoE3, and ApoE4 differ in their abilities to facilitate cholesterol efflux from cells and if ApoE3 and ApoE4 differ in their effects on atherosclerotic lesion formation and regression. Here they will examine the ability of plasma from ApoE-/- mice with macrophage-specific expression of ApoE2, ApoE3, or ApoE4 to induce cholesterol efflux from cholesterol-loaded cells. They will compare the ability of peritoneal macrophages and of stably transfected cells expressing ApoE2, ApoE3, or ApoE4 to release cholesterol. They will determine the mechanism of the differential abilities of ApoE3 and ApoE4 to promote cholesterol efflux and to form gammaLPE (a lipid-poor lipoprotein particle with gamma- electrophoretic motility that contains apoE as its only apolipoprotein constituent). Finally they will examine the effect of macrophage- specific expression of ApoE4 on atherosclerosis development and regression.